Fluvoxamine, an anti-depressant, inhibits human glioblastoma invasion by disrupting actin polymerization

Keiichiro Hayashi, Hiroyuki Michiue, Hiroshi Yamada, Katsuyoshi Takata, Hiroki Nakayama, Fan Yan Wei, Atsushi Fujimura, Hiroshi Tazawa, Akira Asai, Naohisa Ogo, Hiroyuki Miyachi, Tei-ichi Nishiki, Kazuhito Tomizawa, Kohji Takei, Hideki Matsui

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Glioblastoma multiforme (GBM) is the most common malignant brain tumor with a median survival time about one year. Invasion of GBM cells into normal brain is the major cause of poor prognosis and requires dynamic reorganization of the actin cytoskeleton, which includes lamellipodial protrusions, focal adhesions, and stress fibers at the leading edge of GBM. Therefore, we hypothesized that inhibitors of actin polymerization can suppress GBM migration and invasion. First, we adopted a drug repositioning system for screening with a pyrene-actin-based actin polymerization assay and identified fluvoxamine, a clinically used antidepressant. Fluvoxamine, selective serotonin reuptake inhibitor, was a potent inhibitor of actin polymerization and confirmed as drug penetration through the blood-brain barrier (BBB) and accumulation of whole brain including brain tumor with no drug toxicity. Fluvoxamine inhibited serum-induced ruffle formation, cell migration, and invasion of human GBM and glioma stem cells in vitro by suppressing both FAK and Akt/mammalian target of rapamycin signaling. Daily treatment of athymic mice bearing human glioma-initiating cells with fluvoxamine blocked tumor cell invasion and prolonged the survival with almost same dose of anti-depressant effect. In conclusion, fluvoxamine is a promising anti-invasive treatment against GBM with reliable approach.

Original languageEnglish
Article number23372
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - Mar 18 2016

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Fluvoxamine
Glioblastoma
Polymerization
Actins
Brain Neoplasms
Glioma
Drug Repositioning
Stress Fibers
Focal Adhesions
Survival
Serotonin Uptake Inhibitors
Brain
Sirolimus
Drug-Related Side Effects and Adverse Reactions
Blood-Brain Barrier
Actin Cytoskeleton
Nude Mice
Antidepressive Agents
Cell Movement
Stem Cells

ASJC Scopus subject areas

  • General

Cite this

Fluvoxamine, an anti-depressant, inhibits human glioblastoma invasion by disrupting actin polymerization. / Hayashi, Keiichiro; Michiue, Hiroyuki; Yamada, Hiroshi; Takata, Katsuyoshi; Nakayama, Hiroki; Wei, Fan Yan; Fujimura, Atsushi; Tazawa, Hiroshi; Asai, Akira; Ogo, Naohisa; Miyachi, Hiroyuki; Nishiki, Tei-ichi; Tomizawa, Kazuhito; Takei, Kohji; Matsui, Hideki.

In: Scientific Reports, Vol. 6, 23372, 18.03.2016.

Research output: Contribution to journalArticle

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AU - Nakayama, Hiroki

AU - Wei, Fan Yan

AU - Fujimura, Atsushi

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